The transforming growth factor 2 (TGF2) superfamily, the largest family of secreted proteins in mammals, includes the bone morphogenetic proteins (BMPs), actives, and myostatin. These ligands signal through a heteromeric complex of type 1 and type 2 serine/threonine kinase receptors. Ligand-induced dimerization of these receptors leads to phosphorylation of receptor-regulated SMAD proteins, which translocate to the nucleus with SMAD4 to regulate gene expression. These signaling pathways have been implicated in many pathophysiologic processes. For example, at the end of the first trimester, activin A levels are elevated in women who will eventually develop preeclampsia, and the BMP/activin/myostatin type 2 receptor, ACVR2A, has been identified as a candidate maternal susceptibility gene for preeclampsia. With the support of this grant that started in 1994, we have generated and analyzed mice with mutations in activin subunits, a ligand binding protein (follistatin), a downstream receptor-binding protein (FKBP12), several SMADs, and multiple BMP/activin/myostatin receptors. The phenotypes of our genetic models range from neonatal lethality to infertility to cancer. These models have been indispensable for deciphering TGF2 superfamily signaling pathways in the gonads and modeling clinical reproductive diseases including infertility, premature ovarian failure, and ovarian and testicular cancer. These HD32067-supported studies have resulted in 43 papers published during the current grant period and 87 publications overall including high impact papers in Nature, Nature Genetics, Nature Medicine, Science, Genes and Development, and Developmental Cell. The overall goals of this R01 renewal will be to follow-up these studies by analyzing the unique and redundant roles of the type 1 and type 2 receptors in BMP signaling in the uterus and identifying new agents for inhibiting and/or mimicking the functions of BMPs, activins and myostatin in uterine, ovarian, muscle, and bone physiology. The Specific Aims of these proposed studies are: 1) Define the BMP receptor pathways in implantation and post- implantation uterine biology, and 2) Identify and synthesize small molecule BMP receptor-specific antagonists and agonists. These proposed studies will allow us to genetically place TGF2 superfamily ligands, receptors, and downstream SMADs into biological pathways in the female reproductive tract, and identify and synthesize compounds for future treatments of human reproductive and non-reproductive diseases. PUBLIC HEALTH RELEVANCE: The transforming growth factor 2 (TGF2) superfamily is the largest family of secreted proteins in mammals, and TGF2 signaling pathways have been implicated in a diversity of developmental and pathophysiological processes including preeclampsia. Over the last 19 years, we have used multiple in vivo and in vitro approaches to dissect the essential and redundant roles of these signaling pathways. The objectives of this R01 renewal are to mechanistically define the unique and redundant roles of the bone morphogenetic protein (BMP) type 1 and type 2 receptors during implantation and post-implantation and to identify new drugs for inhibiting or mimicking the functions of BMPs, activins, and myostatin for treatments of clinically important reproductive and non-reproductive diseases.